{
  "abstract": "Background T cells expressing CD19-specific chimeric antigen receptors (CARs) mediate high complete response rates in patients with B cell malignancies. However, autologous cell products are costly and time-consuming to produce and demonstrate variability in potency and toxicity. Monomorphic CD1d-restricted Vα24-invariant natural killer T cells (NKTs) are not alloreactive like HLA-restricted T cells and therefore can be made from allogeneic donors without risking graft-versus-host disease.Methods We generated a bank of healthy donor NKTs that co-express a CD19-specific CAR, IL-15, and shRNA targeting beta-2-microglobulin and CD74 to downregulate HLA class I and II expression, respectively. Five lots of allogeneic CD19-CAR-NKTs have been produced for this bank with each lot averaging 14.8 ± 2.5 days in culture, yielding 1.18 - 2.27x10 10 cells per lot and an average NKT purity of 98.99% ± 1.02%. We are assessing the safety, persistence, and efficacy of this allogeneic product in ANCHOR (NCT00840853), a first-in-human phase 1 dose-escalation trial for patients with relapsed/refractory B cell non-Hodgkin’s lymphoma (NHL) and relapsed acute B lymphoblastic leukemia (ALL).Results Nine NHL patients have been infused on three dose levels (DLs: 1x10 7 (DL1), 3x107(DL2), and 1x108 (DL3) CAR-NKT cells/m2) and three ALL patients have been infused on DL1. No dose-limiting toxicities related to CAR-NKTs have been observed. Two cases of grade 2 or lower CRS and one case of grade 3 neurotoxicity have been observed, but in all instances resolved quickly. Four out of nine NHL patients achieved an initial partial response four-to-six weeks after infusion that in two cases evolved into a complete response (CR) by three months post-infusion (patients NHL-2 and NHL-4). Additionally, two out of three ALL patient (ALL-1, ALL-3) achieved an objective response. We detected expansion of CAR-NKTs in the peripheral blood of patients NHL-5 (DL2), NHL-7 and NHL-9 (DL3) that peaked one week after infusion, and CAR-NKTs were also found in biopsied tumor tissue from patient NHL-3 at one week and NHL-2 and NHL-8 at five weeks post-infusion. In patient NHL-2, who achieved a CR at three months post-infusion, we detected a population of recipient NKTs that underwent a 2000-fold expansion event, with numbers peaking at six weeks post-infusion and remaining elevated through 12 weeks.Conclusions Our data indicate that allogeneic CAR-NKTs are well tolerated and can mediate objective responses in NHL/ALL patients that relapsed following multiple salvage protocols, including commercial CAR-T products. Thus, NKTs represent a promising platform for ‘off-the-shelf’ cancer immunotherapy.Trial Registration NCT00840853Ethics Approval This study was approved by the Institutional Review Board at Baylor College of Medicine (BCM; H-44526).",
  "authors": [
    {
      "affiliations": [
        "Baylor College of Medicine, Houston, TX, USA"
      ],
      "name": "Amy N Courtney"
    },
    {
      "affiliations": [
        "Baylor College of Medicine, Houston, TX, USA"
      ],
      "name": "Carlos Ramos"
    },
    {
      "affiliations": [
        "Baylor College of Medicine, Houston, TX, USA"
      ],
      "name": "David Steffin"
    },
    {
      "affiliations": [
        "Baylor College of Medicine, Houston, TX, USA"
      ],
      "name": "Akshaya Adaikkalavan"
    },
    {
      "affiliations": [
        "Baylor College of Medicine, Houston, TX, USA"
      ],
      "name": "Claudia Martinez Amador"
    },
    {
      "affiliations": [
        "Baylor College of Medicine, Houston, TX, USA"
      ],
      "name": "Mahshid S Azamian"
    },
    {
      "affiliations": [
        "Baylor College of Medicine, Houston, TX, USA"
      ],
      "name": "Malcolm K Brenner"
    },
    {
      "affiliations": [
        "Baylor College of Medicine, Houston, TX, USA"
      ],
      "name": "Helen E Heslop"
    },
    {
      "affiliations": [
        "Baylor College of Medicine, Houston, TX, USA"
      ],
      "name": "Leonid S Metelitsa"
    }
  ],
  "title": "553 A phase I clinical trial of allogeneic NKT cells expressing a CD19-specific CAR in patients with relapsed or refractory B cell malignancies: an interim analysis",
  "uid": "64d191b1-b9bb-5855-bc84-5e0f49469f38"
}